Steroid hormone receptors are ligand-dependent transcription factors that require the dynamic, ordered assembly
of multimeric chaperone complexes to reach a functional conformation. Heat shock protein (Hsp) 70 and Hsp90 serve
as the central chaperones that mediate this process in conjunction with a variety of co-chaperones. Many of these cochaperones
represent potential therapeutic targets for the disruption of Hsp90 client protein function. FKBP52 is an
Hsp90-associated co-chaperone that has emerged as a promising therapeutic candidate due to its functional specificity for
a small subset of Hsp90 client proteins including androgen (AR), glucocorticoid (GR), and progesterone (PR) receptors.
Given its Hsp90-client protein specificity, the targeting of FKBP52 should be more specific and less toxic than the Hsp90-
targeting drugs. Additionally, the fkbp52-deficient mice display specific phenotypes related to androgen, progesterone,
and glucocorticoid insensitivity suggesting minimal off-target effects. Finally, the fact that FKBP52 is already a validated
target of the clinically approved immunosuppressive drug, FK506 (Tacrolimus), indicates that FKBP52 is a “druggable”
protein. Thus, the development of FKBP52-specific small molecule inhibitors is predicted to be a highly targeted strategy
with potential for the treatment of any disease that is dependent on a functional AR, GR, and/or PR signaling pathway.
Much progress has been made in understanding the residues and domains critical for FKBP52 function. The proline-rich
loop overhanging the FKBP52 FK1 catalytic domain is functionally important and likely represents an interaction surface
within the receptor-chaperone complex. Thus, the targeting of FKBP52 proline-rich loop interactions is the most attractive
therapeutic approach to disrupt FKBP52 regulation of receptor activity in steroid hormone receptor-dependent physiology